Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial

Abstract

Background: In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.

Methods and results: We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.

Conclusions: TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.

Clinical trial registration: URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Keywords: anticoagulants; arrhythmia; embolism; prevention; risk factors.

Figure 1.

Schematic diagram comparing imputation of international normalized ratio (INR) values between pairs of INR tests using the Rosendaal linear interpolation approach (in red) versus a dose change–based approach (in blue). In this diagram, the target INR range is 2.0 to 3.0 and is highlighted in gray. Points A to F represent INR test results. Points A and B are both in range, and points C and D are both out of range. Since point B is in range, there will be no dose change between B and C. As a result, the 2 imputation approaches do not differ between points A through D. At point D, the INR is above range and a dose change is made resulting in the below‐range INR at point E (an “overshoot”). The imputation of INR values will differ by algorithm as illustrated (see Methods), with the result that the individual patient time in the therapeutic range (iTTR) (time in the gray range) will be lower using the dose change‐based algorithm. The path from point E to point F illustrates an out‐of‐range to in‐range transition (a “correction”). For such transitions, the dose change–based algorithm will impute a larger iTTR. Across a group of individuals, the difference in mean iTTR according to the 2 imputation approaches will depend on the net effect of corrections versus overshoots.

Figure 2.

The mean individual patient time in the therapeutic range (iTTR) as calculated by the Rosendaal and dose change–based algorithms, stratified by geographic region. iTTR is measured as percent. Dose changes were inferred using 2 different approaches, the “assumed” or sensitive approach, and the “evident” or specific approach (see Methods). In addition, dose changes were assumed to be triggered at 2 different sets of thresholds: <2.0 or >3.0 and <1.8 or >3.2 (see Methods). OOR indicates outside of range.